Although the pathogenesis of chronic hepatitis C is poorly understood, recent studies implicate the dynamic interactions which occur between HCV and the infected host as key determinants of viral persistence and disease progression. Studies in humans indicate that genetic evolution of HCV to form viral quasispecies, and the strength of host CD4 and CDS response against HCV antigens are both critically linked to persistence of infection and progression of chronic liver disease. However, research confirming a direct interplay between HCV evolution and the immune responses of individual patients with specific outcomes needs to be performed. The overall goal of this proposal is to gain a better understanding of the pathogenesis of hepatitis C by investigating the relationships between HCV genetic evolution and host immune responses as they relate to resolution or persistence of infection and progression or non- progression of chronic liver disease. We will study subjects from the Alaska Native and American Indian cohort, taking advantage of a serum bank which dates back over 30 years and a large clinical and virological database compiled on approximately 1000 subjects over the past 8 years. HCV genetic evolution will be studied in the context of host immune responses in different clinical settings. Results from these studies will further our understanding of the mechanisms of HCV persistence and liver disease progression.